Alzheimer Disease (AD) is a neurodegenerative disorder characterized by the progressive loss of memory and cognitive functions. Cardinal pathological changes found in the brain of patients with AD are neurofibrillary tangles and deposits of aggregated amyloid protein (Abeta) in neuritic plaques and cerebral vessels (cerebrovascular amyloid angiopathy). The pathogenetic mechanisms that lead to development of AD are not clearly understood. There is no satisfactory treatment for AD. Approximately 10% of AD cases are classified as early onset familial AD (FAD) and show autosomal dominant inheritance. Inherited mutations in the gene coding for presenilin 1 (PS1) cause 18 to 50% of the early onset FAD cases. Although PS1 may be a transmembrane aspartyl protease that generates Abeta by cleaving its precursor proteins, neither the physiological functions nor normal metabolism of PS1 are fully understood. Such understanding is essential to establishing the logical basis for therapy and prevention of the disease. Attempts to clarify the physiological functions of PS1 by constructing PS1 deficient (knockout) mice resulted in embryonic lethality. Thus, it is impossible to study the physiological functions and pathogenetic roles of PS1 in the adult using the "conventional" knockout mice. The primary goal of this pilot project is to establish new lines of PS1 knockout mice where expression of the PS1 gene is tightly regulated by the tetracycline (Tc) controllable transactivator system. The Specific Aims of the current research project are to: (Aim 1) isolate targeted embryonic stem (ES) cell lines with a PS1 gene under control of the Tc transactivator system and (Aim 2) establish mutant mouse lines for the PS1 gene using the targeted ES cell lines established in Aim 1 and test the tight regulation of the targeted PS1 genes in the mice. In these new lines of mice, expression of the PS1 gene will be turned on during embryogenesis and completely turned off by administration of doxycycline (a derivative of Tc) when the mice become adult. The long-term goal of this research is to elucidate the role of PS1 in the pathogenesis of AD via a thorough understanding of the physiological functions and normal metabolism of PS1.